A novel Gly to Arg substitution at position 388 of the alpha1 chain of type I collagen in lethal form of osteogenesis imperfecta

Cultured skin fibroblasts from a proband with a lethal form of osteogenesis imperfecta produce two forms of type I collagen chains, with normal and delayed elec- trophoretic migration; collagen of the proband's mother was normal. Peptide map­ping experiments localized the structural defect in the proband to a 1(I) CB8 peptide in which residues 123 to 402 are spaned. Direct sequencing of amplified cDNA covering this region revealed a G to A single base change in one allele of the al(I) chain, that converted glycine 388 to arginine. Restriction enzyme digestion of the RT-PCR prod­uct was consistent with a heterozygous COL1A1 mutation. The novel mutation con­forms to the linear gradient of clinical severity for the αl(I) chain and results in re­duced thermal stability by 3°C and intracellular retention of abnormal molecules.